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Serum Biomarkers for Discrimination between Hepatitis C-Related Arthropathy and Early Rheumatoid Arthritis

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Serum Biomarkers for Discrimination between Hepatitis C-Related Arthropathy and Early Rheumatoid Arthritis
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    International Journal of   Molecular Sciences  Article Serum Biomarkers for Discrimination betweenHepatitis C-Related Arthropathy and EarlyRheumatoid Arthritis Isabela Silo¸si  1  , Lidia Boldeanu  2,3  , Viorel Biciu¸sc ă  4  , Maria Bogdan  5  , Carmen Avramescu  2  ,Citto Taisescu  4  , Vlad Padureanu  4  , Mihail Virgil Boldeanu  1,3, *, Anica Dricu  6 andCristian Adrian Silo¸si  7 1 Department of Immunology-Laboratory of Immunology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, Craiova 200349, Romania; isabela_silosi@yahoo.com 2 Department of Microbiology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street,Craiova 200690, Romania; barulidia@yahoo.com (L.B.); c.avramescu@yahoo.com (C.A.) 3 Medico Science SRL-Stem Cell Bank Unit, 1B Brazda lui Novac Street, Craiova 200690, Romania 4 Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street,Craiova 200690, Romania; biciuscaviorel@gmail.com (V.B.); taisescu@yahoo.com (C.T.);vldpadureanu@yahoo.com (V.P.) 5 Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street,Craiova 200349, Romania; bogdanfmaria81@yahoo.com 6 Department of Functional Sciences, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street,Craiova 200690, Romania; anica.dricu@live.co.uk 7 Department of Surgery, Faculty of Medicine, University of Medicine and Pharmacy of Craiova,2 Petru Rares Street, Craiova 200349, Romania; cristian_silosi@yahoo.fr *  Correspondence: mihail.boldeanu@umfcv.ro; Tel.: +40-724-515-810Received: 16 May 2017; Accepted: 14 June 2017; Published: 19 June 2017 Abstract:  In the present study, we aimed to estimate the concentrations of cytokines (interleukin 6, IL-6, tumor necrosis factor- α  , TNF- α  ) and auto-antibodies (rheumatoid factor IgM isotype, IgM-RF, antinuclear auto-antibodies, ANA, anti–cyclic citrullinated peptide antibodies IgG isotype, IgGanti-CCP3.1, anti-cardiolipin IgG isotype, IgG anti-aCL) in serum of patients with eRA (early rheumatoid arthritis) and HCVrA (hepatitis C virus-related arthropathy) and to assess the utility of  IL-6, TNF- α  together with IgG anti-CCP and IgM-RF in distinguishing between patients with trueeRA and HCVrA, in the idea of using them as differential immunomarkers. Serum samples were collected from 54 patients (30 diagnosed with eRA-subgroup 1 and 24 with HCVrA-subgroup 2) and from 28 healthy control persons. For the evaluation of serum concentrations of studied cytokinesand auto-antibodies, we used immunoenzimatique techniques. The serum concentrations of bothproinflammatory cytokines were statistically significantly higher in patients of subgroup 1 andsubgroup 2, compared to the control group (  p  < 0.0001). Our study showed statistically significantdifferences of the mean concentrations only for ANA and IgG anti-CCP between subgroup 1 and subgroup2. WealsoobservedthatIL-6andTNF- α   bettercorrelatedwithauto-antibodiesinsubgroup 1 than in subgroup 2. In both subgroups of patients, ROC curves indicated that IL-6 and TNF- α  have a higher diagnostic utility as markers of disease. In conclusion, we can say that, due to high sensitivityfordiagnosticaccuracy,determinationofserumconcentrationsofIL-6andTNF- α  ,possibly in combination with auto-antibodies, could be useful in the diagnosis and distinguishing betweenpatients with true eRA and HCV patients with articular manifestation and may prove useful in the monitoring of the disease course. Keywords:  hepatitis C virus-related arthritis; early rheumatoid arthritis; interleukin 6; tumor necrosis factor- α  Int. J. Mol. Sci.  2017 ,  18 , 1304; doi:10.3390/ijms18061304 www.mdpi.com/journal/ijms  Int. J. Mol. Sci.  2017 ,  18 , 1304 2 of 14 1. Introduction Chronic hepatitis diseases have multifactorial etiology. The experimental data and clinicalobservations have shown that the prevalence of chronic liver infections with hepatitis C virus(HCV) is about 3% [ 1 ]. Besides the primary effects manifested in the liver, chronic HCV infectionmay be associated with various extrahepatic manifestations (approximately 40–70%), such as arthralgias, arthritis, vasculitis, paresthesia, myalgia, pruritus, sicca syndrome, cryoglobulinemia and glomerulonephritis. Hence, we ought to differentiate between chronic HCV infection and primitive rheumatic disease [2,3]. Studies have shown that the prevalence of hepatitis C virus-related arthropathy (HCVrA) is about4%of patients presenting with HCV. This is a small percentage because many patients are diagnosed ashavinganarticular event onlywhenconsultingaspecialist. Polyarthritis, similarlyto earlyrheumatoid arthritis (eRA), is symmetrical, involving mainly small joints but not associated with articular bonyerosions [ 4 ]. Poanta L. et al. undertook a prospective study in which presented evidence that 20% of patients infected with HCV will have arthralgia in first year [ 5 ]. It has been observed that articular manifestations present in patients with HCV are rheumatoid arthritis type or arthritis associated with deposits of cryoglobulines. These patients have a high prevalence of positive rheumatoid factor (RF) and therefore can often be wrongly diagnosed with eRA [6]. Because both eRa and HCVrA are complex disorders with multifactorial etiology, in clinic, diagnosis problems may occur. One of the diagnosis problems is represented by the differentiation of  eRA from HCVrA: the signs and symptoms of HCVrA, including joint involvement, can be similarto eRA, making the distinction between HCVrA and eRA difficult [ 7 , 8 ]. Moreover, the presence of erosions, rheumatoid nodules, or positive anti–cyclic citrullinated peptide antibodies (anti-CCP) ina patient, should generate the possible diagnosis of eRA. It is possible for HCV patients to develop nonerosive arthritis without nodules, and it can also imitate eRA, so, if the erosions are not observed, the discrimination is unable to be made easily [9,10]. The objective of this study was to estimate the concentrations of cytokines (interleukin 6, IL-6and tumor necrosis factor- α  , TNF- α  ) and auto-antibodies (rheumatoid factor IgM isotype, IgM-RF, antinuclear auto-antibodies (ANA), anti-CCP antibodies IgG isotype, IgG anti-CCP3.1, anti-cardiolipinIgG isotype, IgG anti-aCL) in serum of patients with eRA and HCVrA and to assess the utility of IL-6,TNF- α  together with IgG anti-CCP and IgM-RF in distinguishing between patients with true eRA and HCVrA, with the idea of using them as differential immunomarkers. 2. Results 2.1. Clinical Characteristics of the Study Subjects Among the 30 patients initially diagnosed with eRA (subgroup 1), 80% were female (sex ratio: 24 female/6 male), with age, mean ± stdv 55.77 ± 10.87 years. In the HCVrA subgroup (subgroup 2), afemale to male ratio was 14/10 (67%), mean age was 54.42 ± 7.49 years. In the control group, incidence for women was 78% and age 52.36 ± 13.38 years. There was no significant difference in age between the two subgroups (  p  = 0.342) (Table 1). Table 1.  Clinical characteristics of the study subjects. Character eRA Subgroup 1( n  = 30)HCVrA Subgroup 2( n  = 24)  p  Value Controls ( n  = 28) Age (years) (mean ± stdv) 55.77 ± 10.87 54.42 ± 7.49  p  = 0.342 52.36 ± 3.38Gender (female /male) 24/6 (80%) 14/10 (67%)  −  22/6 (78.5%)CRP (mg/dL) 16.97 ± 5.14 16.27 ± 8.24  p  < 0.0001 4.75 ± 2.15 ESR  (mm/1st h) 33.60 ± 12.35 15.71 ± 6.33  p  < 0.0001 11.68 ± 6.24Cryoglobulinemia 13.33% 28%  Int. J. Mol. Sci.  2017 ,  18 , 1304 3 of 14 2.2. Cytokines Concentrations In our study, we found that both proinflammatory cytokines IL-6 (38.77 pg/mL, 95% CI: 26.93–50.60) and TNF- α  (63.32 pg/mL, 95% CI: 45.39–81.26) concentrations in the serum of patients insubgroup 1 were higher than those in the control group (2.85 pg/mL, 95% CI: 2.08–3.62,  p  < 0.0001 and4.29 pg/mL, 95% CI: 3.33–5.25,  p  < 0.0001, respectively). We also found statistical differences between serum concentrations of IL-6 (29.13 pg/mL, 95% CI: 20.01–38.24) and TNF- α  (54.63 pg/mL, 95% CI: 36.50–72.76) of patients in subgroup 2 and the control group (  p  < 0.0001) (Table 2). When we compared the mean concentrations of IL-6 and TNF- α   between the two subgroups, wenoticed that we have no statistically significant differences (  p  = 0.388, respectively  p  = 0.481) (Figure 1).   Concentrations of IL-6 and TNF-   in two subgroups ControlsRAHCVrAControlsRAHCVrA050100150050100150200    I   L  -   6  p  g   /  m   L T NF -    p g /  mL  Figure1.  Interleukin6(IL-6)andtumornecrosisfactor- α  (TNF- α  )concentrationsinserumofpatientsin both subgroups and control group (Black circles represent IL-6 and TNF- α  concentration of individual serum samples; red lines represent mean values accompanied by 95% confidence interval; 95% confidence interval is represented by black horizontal bars). In the studied cohort of patients, we observe statistically significant differences in theconcentrations of CRP and the levels of ESR between both subgroups and the control group(CRP/control group-  p  < 0.0001, ESR/control group-  p  < 0.0001) (Table 1). Comparing the mean concentrationsofCRPandESRbetweenthetwosubgroups,wenoticedthatwehavehighlystatistically significant differences between subgroup 1 and subgroup 2 (  p  < 0.0001). 2.3. Auto-Antibodies Concentrations Another objective of our study was to investigate auto-antibodies profile in both subgroups. In Table 2, we reproduced concentrations of these auto-antibodies investigated. Following the analysis, our study showed statistically significant differences of the meanconcentrations only for ANA and IgG anti-CCP between subgroup 1 and subgroup 2 (ANA,subgroup 1/ subgroup 2-  p  = 0.006, respectively IgG anti-CCP subgroup 2/subgroup 1-  p  < 0.0001) (Table 2). 2.4. Correlations Between IL-6, TNF- α  and Auto-Antibodies in eRA and HCVrA Concentrations of both cytokines are correlated with each other in subgroup 1 ( r  = 0.337,  p  = 0.049)and not correlated in subgroup 2 ( r  = − 0.154,  p  = 0.471) (Tables 3 and 4). In addition, we observed that IL-6 and TNF- α   better correlated with auto-antibodies in subgroup 1 than in subgroup 2.  Int. J. Mol. Sci.  2017 ,  18 , 1304 4 of 14 Table 2.  IL-6, TNF- α  and auto-antibodies (antinuclear auto-antibodies—ANA, anti–cyclic citrullinated peptide antibodies IgG isotype, IgG anti-CCP, anti-cardiolipin IgG isotype, IgG anti-aCL, rheumatoid factor IgM isotype, IgM-RF) concentrations in serum of patients with eRA, HCVrA and in the control group. Parameter(Mean, 95% CI)Levels in Subgroup 1 Levels in Subgroup 2 Levels in SubgroupsRA Control  p  HCVrA Control  p  RA HCVrA  p IL-6 (pg/mL) 38.77 (26.93–50.60) 2.85 (2.08–3.62) < 0.0001 29.13 (20.01–38.24) 2.85 (2.08–3.62)  < 0.0001  38.77 (26.93–50.60) 29.13 (20.01–38.24) = 0.388TNF- α  (pg/mL) 63.32 (45.39–81.26) 4.29 (3.33–5.25) < 0.0001 54.63 (36.50–72.76) 4.29 (3.33–5.25)  < 0.0001  63.32 (45.39–81.26) 54.63 (36.50–72.76) = 0.481ANA (U/mL) 12.43 (9.35–15.52) 4.55 (3.84–5.28) < 0.0001 17.67 (15.76–19.58) 4.55 (3.84–5.28)  < 0.0001  12.43 (9.35–15.52) 17.67 (15.76–19.58) = 0.006IgG anti-CCP (U/L)  100.40 (69.45–131.30)  5.75 (4.34–7.16) < 0.0001 16.99 (14.92–19.07) 5.75 (4.34–7.16)  < 0.0001  100.40 (69.45–131.30)  16.99 (14.92–19.07) < 0.0001IgM-RF (U/L) 65.27 (45.71–84.83) 5.07 (3.95–6.19) < 0.0001 44.42 (31.88–56.96) 5.07 (3.95–6.19)  < 0.0001  65.27 (45.71–84.83) 44.42 (31.88–56.96) = 0.276IgG anti-aCL (U/mL) 13.97 (11.19–16.74) 5.82 (4.41–7.24) < 0.0001 16.12 (12.85–19.38) 5.82 (4.41–7.24)  < 0.0001  13.97 (11.19–16.74) 16.12 (12.85–19.38) = 0.346CRP (mg/dL) 16.97 (15.06–18.89) 4.75 (3.92–5.59) < 0.0001 16.27 (12.79–19.75) 4.75 (3.92–5.59)  < 0.0001  16.97 (15.06–18.89) 16.27 (12.79–19.75) < 0.0001ESR (mm/1st h) 33.60 (28.99–38.21)  11.68 (9.47–14.31)  < 0.0001 15.71 (13.04–18.39)  11.68 (9.47–14.31)  < 0.0001  33.60 (28.99–38.21) 15.71 (13.04–18.39) < 0.0001 Table 3.  Correlations between IL-6, THF- α  and early rheumatoid arthritis (eRA) indices. Parameter ANA IgG Anti-aCL IgM-RF IgG Anti-CCP IL-6 TNF- α   CRP ESR ANA  r  = − 0.069  p  = 0.717 r  = 0.273  p  = 0.145 r  = − 0.157  p  = 0.407 r  = − 0.026  p  = 0.890 r  = 0.076  p  = 0.688 r  = 0.251  p  = 0.181 r  = 0.089  p  = 0.639IgG anti-aCL  r  = − 0.320  p  = 0.049  * r  = 0.052  p  = 0.784 r  = 0.158  p  = 0.460 r = 0.349 p = 0.050 * r  = 0,129  p  = 0.496 r  = 0.274  p  = 0.142IgM-RF  r  = 0.418  p  = 0.022  * r  = − 0.231  p  = 0.219 r  = − 0.131  p  = 0.492 r  = 0.294  p  = 0.115 r  = 0.071  p  = 0.709IgG anti-CCP  r  = 0.371  p  = 0.044  * r  = − 0.231  p  = 0.219 r  = − 0.039  p  = 0.837 r  = − 0.005  p  = 0.979IL-6  r  = 0.337  p  = 0.049  * r  = 0.017  p  = 0.928 r  = 0.029  p  = 0.877TNF- α   r = − 0.404  p  = 0.027  * r  = 0.112  p  = 0.557CRP  r  = − 0.020  p  = 0.916 r  Pearson correlation coefficient, * Statistically significant correlations.  Int. J. Mol. Sci.  2017 ,  18 , 1304 5 of 14 Table 4.  Correlations between IL-6, THF- α  and hepatitis C virus-related arthropathy (HCVrA) indices. Parameter ANA IgG Anti-aCL IgM-RF IgG Anti-CCP IL-6 TNF- α   CRP ESR ANA  r  = 0.649  p  < 0.0001 * r  = 0.077  p  = 0.721 r  = 0.428  p  = 0.037  * r  = − 0.202  p  = 0.345 r  = − 0.160  p  = 0.456 r  = − 0.037  p  = 0.864 r  = 0.303  p  = 0.149IgG anti-aCL  r  = 0.070  p  = 0.744 r  = 0.694  p  < 0.0001  * r  = − 0.056  p  = 0.794 r  = − 0.411  p  = 0.046 * r  = 0.140  p  = 0.515 r  = − 0.050  p  = 0.817IgM-RF  r  = − 0.203  p  = 0.498 r  = 0.578  p  = 0.003 * r  = − 0.052  p  = 0.809 r  = − 0.269  p  = 0.204 r  = 0.210  p  = 0.325IgG anti-CCP  r  = − 0.054  p  = 0.802 r  = − 0.122  p  = 0.571 r  = 0.185  p  = 0.386 r  = − 0.139  p  = 0.516IL-6  r  = − 0.154  p  = 0.471 r  = − 0.101  p  = 0.640 r  = 0.298  p  = 0.158THF- α   r  = 0.050  p  = 0.816 r  = 0.015  p  = 0.944CRP  r  = − 0.342  p  = 0.101 r  Pearson correlation coefficient, * Statistically significant correlation.
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